1. Field of the Invention
This invention relates to imidazo [1,2-a]-quinoline-2-carboxylic acids and derivatives thereof and to their use as antiallergy agents. More particularly, it relates to 5-alkoxyimidazo[1,2-a]quinoline-2-carboxylic acids and derivatives thereof such as esters of the 2-carboxylic acid group, and derivatives of such compounds wherein the benzenoid ring bears up to two substituents; said compounds are useful as agents for the treatment of allergic reactions, especially allergic bronchial asthma; and to certain esters of 5-chloro(and 5-bromo)-imidazo[1,2-a]quinoline-2-carboxylic acids, useful as intermediates for the preparation of said antiallergy agents.
2. Description of the Prior Art
Allergic reactions, the symptoms resulting from an antigen-antibody interaction, manifest themselves in a wide variety of ways and in different organs and tissues. Common allergic disorders, for example, are allergic rhinitis, a condition characterized by seasonal or perennial sneezing, running nose, nasal congestion, with itching and congestion of eyes; hay fever, a variety of allergic rhinitis that results from hypersensitivity to grass polens; and bronchial asthma, one of the most disabling and debilitating of allergic reactions, a disease characterized by hyper-reactivity of the bronchi on exposure to various immunogenic or nonimmunogenic stimuli, resulting in bronchospasms with wheezing, short-lived paroxysms and widespread constriction of airway passages. The mechanical obstruction to airflow in airways is generally reversed by the use of bronchodilators, which provide symptomatic relief. In contrast, antiallergy agents prevent the release of mediators of anaphylaxis from tissue stores, thereby acting in a prophylactic manner to preclude elicitation of bronchoconstriction by the mediators.
Efforts to discover medicinal agents to alleviate the symptoms of the abnormal physiologic state have been extensive. As early as 1910, Matthews, Brit. Med. J., 1, 441 (1910) reported the bronchodilator effects of epinephrine. Since then, Chen and Schmidt, J. Pharmacol. Exper. Therap., 24, 339 (1924) reported the use of the alkaloid ephedrine as an orally efficacious bronchodilator with the same spectrum of activity as epinephrine. In 1940, Konzett, Arch. Exp. Path. Pharmak., 197, 27 (1940) outlined the effects of the potent aerosol bronchodilator isoproterenol. Cullum et al., Brit. J. Pharmacol. Exp., 35, 141 (1969) reported the pharmacology of salbutamol, a potent bronchodilator of prolonged duration, and active via both oral and aerosol administration. Many bronchodilator preparations contain theophylline. These are generally less potent than the sympathomimetic amines such as isoproterenol and salbutamol, and are ineffective in aerosol administration.
Recently, Cox and co-workers, Adv. in Drug Res., 5, 115 (1970), described the pharmacology of the antiallergy agent, disodium cromoglycate [1,3-bis-(2-carboxycromon-5-yloxy)-2-hydroxypropane, Intal]. It is not a bronchodilator, but mediates its therapeutic effects by a unique mechanism of action involving inhibition of release of mediators of anaphylaxis and is administered prophylactically. It suffers from lack of oral efficacy and, for optimum results, is administered by inhalation as a solid inhalant. Further, although it is effective against anaphylaxis due to immunoglubin E (IgE), it is effective against anaphylaxis due to immunoglobulin G (IgG) only at high doses (60-70% protection at 100 and 300 mg./kg.).
Although the aforementioned agents represent outstanding contributions toward the treatment of asthma, many of them exert the undesired side effect of cardiac stimulation.
The first reference to the imidazo[1,2-a]quinoline ring systems appears to be that of U.S. Pat. No. 2,421,693 in which 3-acyl-2-keto-1,2-dihydroimidazo[1,2-a]quinolinium salts and the corresponding 3-alkyl, 3-aryl and 3-aralkyl compounds were claimed to be useful as magenta color formers. The chemistry of the known imidazo[1,2-a]quinolines was reviewed in "The Chemistry of Heterocyclic Compounds", A. Weissberger, Ed., Interscience Publishers, N.Y., 1961, pp. 518-521. The imidazo[1,2-a]quinoline-2-carboxylic acids and derivatives thereof have not previously been reported.